Catalysis of Diketopiperazine Synthesis

ABSTRACT

Provided is a method for the synthesis of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazine including the step of heating a solution of ε-amino protected lysine in the presence of a catalyst selected from the group consisting of sulfuric acid, phosphoric acid, and phosphorus pentoxide.

RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 14/266,632, filed Apr. 30, 2014, which is a continuation ofU.S. patent application Ser. No. 13/422,989, filed Mar. 16, 2012, nowU.S. Pat. No. 8,748,609, which is a divisional of U.S. patentapplication Ser. No. 12/633,673, filed Dec. 8, 2009, now U.S. Pat. No.8,202,992, which is a continuation of U.S. patent application Ser. No.11/208,087, filed Aug. 19, 2005, now U.S. Pat. No. 7,709,639, whichclaims priority under 35 U.S.C. §119(e) to U.S. Provisional PatentApplication No. 60/603,340, filed Aug. 20, 2004, all of which areincorporated by reference herein in their entirety.

FIELD OF THE INVENTION

This invention is generally in the field of chemical synthesis. Moreparticularly it is related to improved syntheses of N-protectedbis-3,6-[4-aminobutyl]-2,5-diketopiperazines.

BACKGROUND TO THE INVENTION

Drug delivery has been a persistent challenge in the pharmaceuticalarts, particularly when a drug is unstable and/or poorly absorbed at thelocus in the body to which it is administered. One such class of drugsincludes 2,5-diketopiperazines having the general structure of Formula1.

These 2,5-diketopiperazines have been shown to be useful in drugdelivery, particularly those bearing acidic R groups (see for exampleU.S. Pat. No. 5,352,461 entitled “Self-assembling diketopiperazine drugdelivery system;” Ser. No. 5,503,852 entitled “Method for makingself-assembling diketopiperazine drug delivery system;” Ser. No.6,071,497 entitled “Microparticles for lung delivery comprisingdiketopiperazine;” and Ser. No. 6,331,318 entitled “Carbon-substituteddiketopiperazine delivery system,” each of which is incorporated hereinby reference in its entirety for all that it teaches regardingdiketopiperazines and diketopiperazine-mediated drug delivery).Diketopiperazines can be formed into particles that incorporate a drugor particles to which a drug can be adsorbed. The combination of a drugand a diketopiperazine can impart improved drug stability. The particlescan be administered by various routes of administration. As dry powdersthese particles can be delivered to specific areas of the respiratorysystem, depending on particle size. The particles can be made smallenough for incorporation into intravenous suspension dosage forms. Oraldelivery is also possible using a suspension, or as particles pressedinto tablets or contained in a capsule. These diketopiperazines can alsofacilitate absorption of the associated drug.

A conventional step in synthesis of 2,5-diketopiperazines includes thepreparation of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazineby thermal condensation of lysine. Conventional commercial manufacturingprocesses utilize (N-benzyloxycarbonyl)-lysine (Cbz-L-lysine) to producebis-3,6-[(N-benzyloxycarbonyl)-4-aminobutyl]-2,5-diketopiperazine(DKP1). This process entails heating Cbz-L-lysine in m-cresol for 18-22hours at 160° C.-170° C., and provides DKP1 in an average yield of about47.5% after recrystallization from glacial acetic acid.

Therefore, it is an object of the present invention to provide improvedmethods of synthesis for diketopiperazines.

SUMMARY OF THE INVENTION

The present invention provides methods for the synthesis ofdiketopiperazines using catalysts such that faster reaction times andhigher yields are achieved compared to conventional step(s)/method(s).Utilizing the catalyst of the present invention, phosphorus pentoxide,in a cyclocondensation reaction, provides for the synthesis ofdiketopiperazines of higher yield and higher purity in shorter reactiontimes over that of conventional step(s)/method(s).

The present invention provides a method for the synthesis of N-protectedbis-3,6-[4-aminobutyl]-2,5-diketopiperazine comprising the step ofheating a solution of ε-amino protected lysine in the presence of acatalyst selected from the group consisting of sulfuric acid (H₂SO₄),phosphoric acid (H₃PO₄), and phosphorus pentoxide (P₂O₅).

One embodiment of the present invention provides a method for thesynthesis of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazinewherein the ε-amino protected lysine is (N-benzyloxycarbonyl)-lysine(Cbz-L-lysine) and the product isbis-3,6-[(N-benzyloxycarbonyl)-4-aminobutyl]-2,5-diketopiperazine(DKP1).

Another embodiment of the present invention provides a method for thesynthesis of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazinewherein the solution is heated to a target temperature of about 160° C.to 170° C. This target temperature is preferably achieved in about 4 to6 hours.

In yet another embodiment of the present invention a method for thesynthesis of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazinecomprising the step of heating a solution of ε-amino protected lysine inthe presence of a catalyst is provided wherein synthesis issubstantially complete within about 10 hours of reaching a targettemperature. More preferably, the synthesis is substantially completewithin about 8 hours, 6 hours, 4 hours, 3 hours, or 2 hours of reachinga target temperature. Most preferably, the synthesis is substantiallycomplete within about 1.5 hours of reaching a target temperature.

Another embodiment of the present invention provides a method for thesynthesis of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazinecomprising the step of heating a solution of an ε-amino protectedlysine, such as (N-benzyloxycarbonyl)-lysine (Cbz-L-lysine), in thepresence of a catalyst, such as phosphorus pentoxide, wherein synthesishas a yield of greater than 50%.

Another embodiment of the present invention provides a method for thesynthesis of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazine inthe presence of the catalyst phosphorus pentoxide the concentration ofphosphorus pentoxide is about 5% to 10%.

These and other objects, advantages and features of the invention willbe more fully understood and appreciated by reference to the writtenspecification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a flow chart of2,5-diketo-3,6-di(4-fumarylaminobutyl)piperazine (fumaryldiketopiperazine, FDKP) retrosynthesis according to one aspect of thepresent invention.

FIG. 2 depicts a flow chart ofbis-3,6-[(N-benzyloxycarbonyl)-4-aminobutyl]-2,5-diketopiperazine (DKP1)synthesis according to one aspect of the present invention.

FIG. 3 depicts the conversion of (N-benzyloxycarbonyl)-lysine)Cbz-L-lysine to DKP1 using the sulfuric acid catalysis methods accordingto one aspect of the present invention.

FIG. 4 depicts the conversion of Cbz-L-lysine to DKP1 using thephosphoric acid catalysis methods according to one aspect of the presentinvention.

FIG. 5 depicts the conversion of Cbz-L-lysine to DKP1 using thephosphorus pentoxide catalysis methods according to one aspect of thepresent invention.

FIG. 6 depicts a comparison of the three catalysts according to oneaspect of the present invention.

FIG. 7 depicts the reaction sequence of the P₂O₅-catalyzedcyclodimerization according to one aspect of the present invention.

FIG. 8 depicts the overall yield of DKP1 versus time using thephosphorus pentoxide catalyst of the present invention (5 liter scalereaction).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for the synthesis ofdiketopiperazines using catalysts such that faster reaction times andhigher yields are achieved compared to conventional step(s)/method(s).Utilizing the catalyst of the present invention, phosphorus pentoxide,in a cyclocondensation reaction, provides for the synthesis ofdiketopiperazines of higher yield and higher purity in shorter reactiontimes over that of conventional step(s)/method(s).

The conventional synthesis of diketopiperazines useful in drug delivery,such as 2,5-diketo-3,6-di(4-fumarylaminobutyl)piperazine (fumaryldiketopiperazine, FDKP), commonly begins from the thermalcyclocondensation of ε-amino protected lysine, for example(N-benzyloxycarbonyl)-lysine (Cbz-L-lysine) (see FIGS. 1 and 2). Theuncatalyzed reaction is lengthy, 18-33 hours, with yields under 50% andin some cases as little as 25%. Such lengthy reactions and relativelylow yields lead to undesirably low reactor throughput in industrialapplications.

It is appreciated that others have used phosphorous pentoxide (P₂O₅) asa catalyst and polyphosphoric acid as the solvent to preparediketopiperazines. For examples see J. Am. Pharm. Assoc, 1957, 46:391-3,Galinsky et al. wherein the authors describe using polyphosphoric acidwith P₂O₅ for the preparation of glycine, alanine, leucine, isoleucineand phenylalanine diketopiperazines; see also ARKIVOC 2001 (ii) p.122-134, Kappe et al. wherein the synthesis of Biginellidihyropyrimidones using P₂O₅ (as the polyphosphate ester) as acyclocondensation/dehydration reagent is described. Additionally see J.Org. Chem., 1961, 26:2534-6, Erlanger, “Phosphorus pentoxide as areagent in peptide synthesis.” Described therein is P₂O₅ (with butanoldiethyl hydrogen phosphite) used as a reagent for making a lineardipeptide from protected amino acid fragments. However, it wassurprisingly discovered by the present inventors that the reactionconditions and solvents described in the above cited references resultedin degradation of the (N-benzyloxycarbonyl)-lysine starting material andthus were incompatible with the teachings of the present invention.Thus, a catalyst that could speed the reaction and generate higheryields was sought.

One embodiment of the present invention includes the incorporation of acatalyst into the above-noted reaction to increase the speed of thereaction and to generate higher yield percentages of the presentinvention. The three following reagents were evaluated for theirusefulness as catalysts for this dehydrative cyclocondensation reaction:sulfuric acid (H₂SO₄), phosphoric acid (H₃PO₄), and phosphorus pentoxide(P₂O₅) using m-cresol as a solvent. The term “substantially complete” asused herein with regard to the synthesis of the present invention refersto at least about 80% of the starting material being consumed within theprescribed time period. Reactions were carried out with each of thepotential catalysts. The consumption of Cbz-L-lysine and the appearanceof bis-3,6-[(N-benzyloxycarbonyl)-4-aminobutyl]-2,5-diketopiperazine(DKP1) were monitored by high performance liquid chromatography (HPLC)at time points throughout this reaction. At selected time points DKP1was isolated and its yield calculated.

The presence of sulfuric acid as a catalyst resulted in a yield of about35%, which is within the range of the uncatalyzed reaction. However,this 35% yield was achieved in only 4 hours (see FIG. 3) as compared tothe conventional uncatalyzed reaction times of from about 18 hours toabout 33 hours to achieve a similar reaction yield percentage.

The phosphoric acid catalyzed reaction was substantially complete inthat it had consumed at least about 80% of the Cbz-L-lysine by aboutthree hours. The DKP1 was stable when evaluated within 4 hours of thereaction and the yield was found to be about 55% (see FIG. 4).

The phosphorus pentoxide catalyzed reaction had consumed about 90% ofthe Cbz-L-lysine by 1 hour and consumed almost all of the Cbz-L-lysineby about 1.5 hours. At this point, the yield was determined to be about60% (see FIG. 5). Thus, all three catalysts significantly increased thespeed of the reaction; and phosphoric acid and phosphorous pentoxidealso increased the yield percentage (see FIG. 6 and Table 1).

TABLE 1 Comparison of catalyzed vs. uncatalyzed DKP1 synthesis CatalystTemperature ° C. Time (hours) % Yield DKP1 None 165 24-33 25-35 H₂SO₄165 4 35 H₃PO₄ 165 4 55 P₂O₅ 165 1.5 60

Solvents suitable for use in the reactions of the present inventioninclude, but are not limited to, m-cresol, ethylene glycol, propyleneglycol, toluene, xylenes and equivalents known to those skilled in theart. Additionally, as will be apparent to persons skilled in the art,various solvents have different boiling temperatures and polarity andtherefore reaction temperatures and reaction times may vary betweensolvents.

EXAMPLES Example 1 Phosphorus Pentoxide Catalyzed Synthesis of3,6-bis[3-(N-benzyloxycarbonyl)aminopropyl]-2,5-diketopiperazine (DKP1a)I

A 4-neck 1-L, round-bottom flask equipped with a mechanical stirrer,thermocouple temperature readout/controller, nitrogen gas inlet, andshort-path distillation apparatus was charged with 100 g ofCbz-ornithine, 7.5 g of phosphorus pentoxide, and 300 mL of m-cresol.The stirrer and nitrogen purge were started. The slurry was heated to165° C.±5° C. After formation of a complete solution (approximately30-60 minutes), the mixture was held at 165° C. for an additional 60minutes. The heating mantle was removed and the solution cooled to 50°C. A quench solution was prepared in a 2000-mL beaker consisting of an80:20 mixture of methanol:water (1000 mL). The warm reaction solutionwas poured into the stirring methanol (MeOH) solution and the resultingsuspension stirred for 30 minutes. The suspension was filtered through amedium porosity sintered glass funnel and the filter cake washedsequentially with 250 mL MeOH, 250 mL deionized water, and 2×250 mLMeOH. The isolated product was dried overnight in a vacuum oven (50° C.,30 inches of mercury). The crude product was recrystallized from aceticacid and dried in a vacuum oven to give 58.5 g (63%) of the desireddiketopiperazine.

Elemental Analysis: Calc C 62.89 H 6.50 N 11.28 Found C 62.15 H 6.64 N11.09

¹H NMR Analysis: (d₆-DMSO):

δ 8.97, 2H (NH); δ 7.28-7.37, 10H (CH); δ 7.08, 2H (NH); δ 5.01, 4H(CH₂); δ 3.79, 2H (CH); δ 2.99-3.01, 4H (CH₂); δ 1.60-1.70, 4H (CH₂); δ1.46-1.57, 4H (CH₂)

Example 2 Phosphorus Pentoxide Catalyzed Synthesis of DKP1 II

A 1-L round bottom flask equipped with a mechanical stirrer, short-pathdistillation apparatus, a thermocouple temperature read-out/controller,and a nitrogen inlet was charged with Cbz-L-lysine (100 g), m-cresol(200 g) and phosphorus pentoxide (7.5 g). The reaction mixture wasstirred, heated to a target temperature of 165° C., and held attemperature for 1.5 hours. See FIG. 7.

After completion of the heating period, the reaction solution wasallowed to cool to room temperature (22-25° C.) and quenched with asolution of deionized water (100 mL) and MeOH (400 mL). The resultingsuspension was stirred for 30-60 minutes and then filtered through amedium porosity sintered glass funnel. The filter cake was washedsequentially with 250 mL MeOH, 2×250 mL deionized water, and 2×250 mLMeOH.

The wet cake was dried in a vacuum oven at 50° C. The recovered materialwas analyzed by HPLC and recrystallized from glacial acetic acid (3mL/gram of crude product) according to the following procedure. Thecrude dry DKP1 in acetic acid was heated to reflux in an Erlenmeyerflask equipped with a thermometer and a reflux condenser with nitrogenhead and outlet connected to a caustic scrubber. After 5 to 10 minutes(to ensure that complete dissolution occurred), the heat was removed andthe mixture cooled to a temperature of less than 100° C. Deionized water(1 mL/gram of crude product) was added to the flask and the resultingsuspension was cooled to room temperature with stirring over a period of6-18 hours. The precipitated solid was filtered through a mediumporosity sintered glass funnel and washed with deionized water (3×100mL) and acetone (3×100 mL). The recrystallized wet cake was dried at 50°C. in a vacuum oven.

Example 3 Optimization of Phosphorus Pentoxide Catalyzed Synthesis ofDKP1

The dehydrative coupling and cyclization of Cbz-L-lysine to form DKP1was evaluated as a function of reaction heating time and P₂O₅ charge.Reactions were carried out using 5%, 7.5% or 10% P₂O₅ (wt/wt based onCbz-L-lysine) with various heating times (Table 2). The data indicatedthat yield and purity were maximized using 7.5% P₂O₅.

Subsequent experiments were designed to identify optimal conditions forthe 7.5% phosphorus pentoxide catalyzed conversion of Cbz-L-lysine toDKP1. Additionally, these reactions were monitored for the disappearanceof Cbz-L-lysine. FIG. 5 shows data obtained from a study in which theCbz-L-lysine/cresol/P₂O₅ (7.5%) reaction mixture was monitored for DKP1formation for 3 hours. During this time the reaction temperature wasmaintained at 165° C.±5° C. Aliquots (3 mL) were removed at specifiedtimes throughout the reaction, quenched with deionized water/methanol,and the product isolated by filtration. HPLC analysis of these samplessuggested that the yield of DKP1 reached a maximum after heating for 1to 3 hours (Table 2). After 4 hours at 165° C.±5° C., a 7-8% decrease inDKP1 yield was observed.

Having identified 1-3 hours as the optimal reaction time, severalreactions (100 g scale) were conducted to measure isolated DKP1 yieldswithin this time period. FIG. 8 shows that the maximum DKP1 isolatedyield (60.9%) was obtained after 1.5 hours. HPLC analysis showed thismaterial to be >99.5% DKP1. This reaction was repeated with comparableresults, namely DKP1 (100.0 area %) was isolated in a 60.3% yield. Thereaction was also performed using heat ramps of 4 hours and 6 hours tosimulate the large volume heating times. These reactions gave yields of59.6% and 63.1%, respectively (Table 2).

TABLE 2 Summary of phosphorus pentoxide studies. Time Overall CBZ periodTemp. Yield Purity Lys (g) % P₂O₅ (hours) ° C. (%) (area %) 100 10.0 0.5165 52.90 100 100 7.5 1   165 53.30 100 100 7.5 1.5 165 60.90 100 1007.5 1.5 165 60.25 100 100 7.5 2   165 59.20 100 100 7.5 2   165 57.90100 100 10.0 2   165 54.50 100 100 7.5 3   165 54.90 100 100 10.0 3  165 48.90 100 100 7.5 4   165 53.30 100 100 7.5 4   165 51.60 100 1007.5  1.5* 165 59.60 100 100 7.5  1.5** 165 63.10 100 *4 hour heat ramp**6 hour heat ramp

The optimized conditions (7.5% P₂O₅, 165° C., 1.5 hours) were thendemonstrated twice at the 5-L scale. Again a 4-hour and a 6-hour rampwere employed to simulate the heating profile employed in productionvolumes. Both reactions reproduced the results obtained at the 1-Lscale. The reactions have overall yields of 58.9% and 58.4% with puritycomparable to the current process (99.8%).

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe present invention. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar references used in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein is merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is hereindeemed to contain the group as modified thus fulfilling the writtendescription of any and all Markush groups used in the appended claims.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on those preferred embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventors expect skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, references have been made to patents and printedpublications throughout this specification. Each of the above citedreferences and printed publications are herein individually incorporatedby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

What is claimed is:
 1. A method for the synthesis of an N-protected 3,6-bis[4-aminoalkyI]-2,5-diketopiperazine comprising heating a solution comprising: a. an amino acid having a free a-amine group and a protected amine group, and b. means for catalyzing dehydrative cyclocondensation of said amino acid.
 2. The method of claim 1 wherein said the solution is heated to a target temperature and the target temperature is achieved in about 4-6 hours.
 3. The method of claim 1, wherein said solution is heated to a target temperature and the target temperature is maintained for up to 6 hours.
 4. The method of claim 1, wherein said solution is heated to a target temperature and wherein said synthesis is substantially complete within about 8 hours of reaching said target temperature.
 5. The method of claim 1, wherein the solution is heated to a target temperature of between 160° C. and 170° C.
 6. The method of claim 1, wherein said means for catalyzing dehydrative cyclocondensation of said amino acid comprises addition of a catalyst to the solution, wherein said catalyst comprises at least one of sulfuric acid, phosphoric acid, or phosphorus pentoxide.
 7. The method of claim 1, wherein the solution further comprises m-cresol, ethylene glycol, propylene glycol, toluene, or xylene.
 8. A method for the synthesis of N-protected 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine comprising: a. a step for catalyzing a dehydrative cyclocondensation reaction of an amino acid having a free a-amine group and a protected amine group, and b. collecting the N-protected 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine on a filter.
 9. The method of claim 8 wherein said dehydrative cyclocondensation reaction comprises heating to a target temperature and the target temperature is achieved in about 4-6 hours.
 10. The method of claim 8, wherein said dehydrative cyclocondensation reaction is heated to a target temperature and the target temperature is maintained for up to 6 hours.
 11. The method of claim 8, wherein said dehydrative cyclocondensation reaction is heated to a target temperature and wherein said synthesis is substantially complete within about 8 hours of reaching said target temperature.
 12. The method of claim 8, wherein said step for catalyzing dehydrative cyclocondensation of said amino acid comprises using at least one of sulfuric acid, phosphoric acid, or phosphorus pentoxide as the catalyst.
 13. The method of claim 8, further comprising heating the amino acid having a free α-amine group and a protected amine group in a solvent to a temperature range of between 160° C. and 170° C.
 14. A method for the synthesis of N-protected 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine comprising: a. adding an amino acid having a free a-amine group and a protected amine group to a solvent, and b. a step for catalyzing dehydrative cyclocondensation of the amino acid having a free a-amine group and a protected amine group
 15. The method of claim 14, wherein said step for catalyzing comprises heating said solvent containing said amino acid to a target temperature and the target temperature is achieved in about 4-6 hours.
 16. The method of claim 14, wherein said step for catalyzing comprises heating said solvent containing said amino acid to a target temperature and the target temperature is maintained for up to 6 hours.
 17. The method of claim 14, wherein said step for catalyzing comprises heating said solvent containing said amino acid to a target temperature and wherein said synthesis is substantially complete within about 8 hours of reaching said target temperature.
 18. The method of claim 14, further comprising heating the amino acid having a free α-amine group and a protected amine group to a temperature range of between 160° C. and 170° C.
 19. The method of claim 14, wherein said step for catalyzing dehydrative cyclocondensation of said amino acid comprises addition of a catalyst to the solution, wherein said catalyst comprises at least one of sulfuric acid, phosphoric acid, or phosphorus pentoxide. 